Natural antimicrobial peptides (AMPs) defend a wide array of organisms against bacterial invaders and show potential as supplements for or replacements of conventional antibiotics, since few bacteria have evolved resistance to them. Many AMPs kill bacteria by permeabilization of the cytoplasmic membrane, causing depolarization, leakage, and death, whereas others target additional anionic bacterial constituents (e.g. DNA, RNA, or cell wall components). Bacterial resistance to AMPs is rare probably because they have evolved along with the resistance mechanisms designed to evade them; furthermore, the targets of many AMPs (e.g. bacterial plasma membranes, anionic intracellular macromolecules) are sufficiently general that changes to their sequence can be made that subvert resistance, yet have negligible impact on overall functionality.
Although AMPs have been actively studied for decades, they have yet to see widespread clinical use. This is in part due to the vulnerability of many peptide therapeutics to rapid in vivo degradation, which dramatically reduces their bioavailability. Non-natural mimics of AMPs can circumvent the proteolytic susceptibility of peptides while retaining their beneficial features. The short (<40 amino acids), simple structure of AMPs in the cationic, linear, α-helical class, which includes the well-known magainins, are especially amenable to mimicry. β-peptide mimics of these AMPs have been successfully created with antibacterial and non-hemolytic in vitro activity. Poly-N-substituted glycines (peptoids) comprise another class of peptidomimetics, and are isomers of peptides in that peptoid side chains are attached to the backbone amide nitrogen rather than to the α-carbon. More than any of the other peptidomimetic systems under study, including β-peptides, β-peptoids, oligoureas, and oligo(phenylene ethynylene)s, peptoids are particularly well-suited for AMP mimicry because they are easily synthesized on solid phase (using conventional peptide synthesis equipment) with access to diverse sequences at relatively low cost. By way of an elegant submonomer synthetic method, any chemical functionality available as a primary amine can be incorporated, whether it be an analog of a proteinogenic amino acid or a totally non-natural moiety; thus, peptoids are highly and finely tunable. Furthermore, they are protease-resistant, and can be designed to form amphipathic helices that resist thermal and chaotropic denaturation.
The poly-N-substituted glycine structure of peptoids precludes both backbone chirality and intrachain hydrogen bonding; nevertheless, peptoids can be driven to form stable helical secondary structures via periodic incorporation of bulky, α-chiral side chains. X-ray, NMR, and CD studies of peptoid oligomers have shown that incorporation of homochiral side chains can give rise to polyproline type-I-like helices with a periodicity of ˜3 monomers per turn and a helical pitch of 6.0-6.7 Å. The three-fold periodicity of the peptoid helix facilitates the design of facially amphipathic structures similar to those formed by many AMPs; for example, the trimer repeat (X-Y-Z)n forms a peptoid helix with three faces, composed of X, Y, and Z residues, respectively.
Amphipathic secondary structures in which residues are segregated into hydrophobic and cationic regions are the hallmark of most AMPs. Regardless of their final target of killing, AMPs must interact with the bacterial cytoplasmic membrane, and amphipathicity is integral to such interactions. The cationic region facilitates electrostatically driven adsorption to anionic bacterial membranes and imparts some measure of selectivity, since mammalian cell membranes are largely zwitterionic. The hydrophobic region provides an additional driving force for incorporation of the AMP into the lipid bilayer. The precise nature of AMP-membrane interactions remains controversial and actively debated; a variety of mechanisms have been proposed, including the carpet, barrel-stave pore, toroidal pore, and aggregate models.